March 14, 2013

Tapeworm Genome Mapped, Search Is On For Targeted Drug Therapies

A research team, led by the Wellcome Trust Sanger Institute, has mapped the genome of tapeworms to reveal potential drug targets for existing drugs. Urgently needed and effective treatments for the debilitating diseases caused by tapeworms could be developed from the new information the genome provides.

Two of the World Health Organization's (WHO) 17 neglected tropical diseases are caused by tapeworms: echinococcosis and cysteicercosis. To explore the genetics and underlying biology of this unusual parasite, the team sequenced the genomes of four separate species of tapeworm. An adult tapeworm can live in a human or animal gut relatively harmlessly, but the larvae can spread throughout the body with devastating effects. They form cysts in the internal organs that proliferate or grow in the body, much like cancer. For some animals, this can cause blindness and epilepsy, among other complications. For other species, it may lead to death.

"Tapeworm infections are prevalent across the world and their devastating burden is comparable to that of multiple sclerosis or malignant melanoma," says Dr Matthew Berriman from the Wellcome Trust Sanger Institute. "These genome sequences are helping us to immediately identify new targets for much-needed drug treatment. In addition, exploring the parasites' full DNA sequences is driving our understanding of its complex biology, helping the research community to focus on the most effective drug candidates."

Normally, to identify new targets for drugs needed to combat diseases, researchers compare a pathogen's genome sequence with the human host's DNA to find differences between them. This time, the team looked for similarities instead because humans and tapeworms are both multicellular and the tapeworm is evolutionarily very similar to humans. By searching for the similarities instead of differences, the team found targets that exploit the activities of existing drugs. Time and money should be saved by identifying treatments already on pharmacy shelves that are approved for other uses.

The team suggests that tapeworms could be susceptible to cancer treatments, such as suppressing cell division and preventing DNA replication, because many of the processes of the tapeworm caused diseases parallel those of cancer. Many of the most likely targets for drug treatment compiled by the team were the same targets as pre-existing cancer chemotherapies.

Other promising targets for existing drugs were revealed by combining biological knowledge with the full genome. Over the course of their evolution, tapeworms have lost the ability to synthesize the necessary fats and cholesterol crucial for larvae development. Tapeworms scavenge and modify these fats and cholesterol from their host, instead. The tapeworm's most active genes are involved in this scavenging process, producing proteins that bind fats or are the precursors of fatty acid binding proteins. The disruption of these proteins with current drugs may prove an effective treatment.

"We have developed new method to grow tapeworm cells in the laboratory and we're screening these cells against many of the potential drug treatments identified from the genomes," says Professor Klaus Brehm, from the University of WÃ¼rzburg, Germany. "Given that so few successful treatment options are currently available, we hope that we will be able to identify and validate existing drug candidates, relieving the burden of this debilitating, overlooked disease."

The team also discovered why other treatments for tapeworms have been unsuccessful. Targeting the acetylcholinesterases (enzymes present in the central nervous system), for example, has proved effective in treating malaria and fluke worms but not against tapeworms.

By analyzing the gene activity, the team showed that the production of acetylcholinesterases is surprisingly low in tapeworm cysts. This explains why their disruption had no effect.
The scientists managed to assemble essentially complete chromosomes for one tapeworm species, revealing a similar chromosomal organization with the distantly related flukes. The team was also able to examine the evolutionary genetic losses and gains of tapeworm because of the quality and high level of genomic sequence in this study. This provided them with hundreds of potential drug targets and eliminating those targets that are unlikely to work against tapeworm infection.

"We need to take advantage of this genetic sequence data to find new and improved ways of coping with this problem that devastates much of the developed and developing world," said Professor Peter Hotez, Dean of the National School of Tropical Medicine at Baylor College of Medicine and Editor-in-Chief of PLoS Neglected Tropical Diseases. "Open access to these complete genomes will accelerate the pace in which we find alternative tools and treatments to combat tapeworm infections."

"These tapeworms have accompanied the human being throughout our recorded history; Taenia solium infections were already known in the times of Confucius in China as well as in the Aristotle's Athens," says Professor Juan P Laclette, from the National University of Mexico. "Counting today with this group of genomes is somehow an historical achievement and is very exciting. New opportunities are open now for the treatment, prevention and control of these neglected diseases affecting a number of developing countries."

"These promising findings offer new hope for huge numbers of people around the world — especially the global poor," said David Walker, President of the American Society of Tropical Medicine and Hygiene. "Findings like this remind us that when public and private financing is threatened or cut for research into diseases like tapeworm that is highly associated with poverty, real people and families are the victims. The public and private sectors must work together to reduce this needless suffering."

The results of this study have been published in a recent issue of Nature.